title: Investigation of viral escape mutations within HCV p7 during treatment with amantadine in patients with chronic hepatitis C.
abstract: BACKGROUND
  Combination of several direct-acting antiviral agents will be necessary to overcome viral resistance in interferon-free treatment regimens for chronic HCV infection. HCV p7 inhibitors may be part of such combination regimens. Understanding why amantadine, despite showing inhibition of HCV p7 in vitro, appears ineffective in clinical trials, may help in the design of novel HCV p7 inhibitors. So far it is unknown whether viral escape mutations within HCV p7 explain the ineffectiveness of amantadine in vivo.
  
  
  METHODS
  Pretreatment HCV p7 was directly sequenced in 157 consecutive patients with chronic HCV genotype 1b infection who had been treated with amantadine/placebo plus pegylated interferon (PEG-IFN)-α2a/ribavirin within a multicentre clinical trial. Triple therapy was preceded by 2 weeks of amantadine/placebo monotherapy. In nine patients, clonal sequencing was performed at baseline and after 2 weeks of amantadine/placebo monotherapy.
  
  
  RESULTS
  Changes of the relative frequency of amino acid substitutions by ≥20% between pretreatment and week 2 of monotherapy were considered potential resistance mutations if they were only found in patients receiving amantadine but not in patients receiving placebo. Seven substitutions fulfilling these criteria were identified in the subset of patients with clonal sequencing. However, none of these substitutions were associated with treatment outcome in the complete cohort of patients receiving triple therapy with amantadine.
  
  
  CONCLUSIONS
  Potential viral escape mutations within HCV p7 do not seem to play a major role for treatment response to antiviral therapy with amantadine and PEG-IFN-α2a/ribavirin in patients with chronic HCV genotype 1b infection.
authors.affiliation: Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Vermehren
authors.forename: Christoph
authors.initials: C
authors.lastname: Welsch
authors.forename: Ulrike
authors.initials: U
authors.lastname: Elsler
authors.forename: Johannes
authors.initials: J
authors.lastname: Vermehren
authors.forename: Eva
authors.initials: E
authors.lastname: Herrmann
authors.forename: Christoph
authors.initials: C
authors.lastname: Sarrazin
authors.forename: Michael
authors.initials: M
authors.lastname: von Wagner
authors.forename: Simone
authors.initials: S
authors.lastname: Susser
authors.forename: Wolf Peter
authors.initials: WP
authors.lastname: Hofmann
authors.forename: Bernd
authors.initials: B
authors.lastname: Kronenberger
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Ulrike
authors.initials: U
authors.lastname: Mihm
mesh_terms: D000547:Amantadine / Q000494:pharmacology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009154:Mutation; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D016415:Sequence Alignment; D016896:Treatment Outcome; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics*; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D016898:Interferon-alpha; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D014764:Viral Proteins; C088369:p7 protein, Hepatitis C virus; D000086082:Viroporin Proteins; C100416:peginterferon alfa-2a